Bottom Line:
The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients.Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Background: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes.

Methods and results: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.

Figure 4: Expression levels of JARID2 (A) and ATXN1 (B) in leucocytes from our four patients with deletion of one or both of these genes (Patients 1-4 and Patients 1-3 and 5, respectively), compared with eight healthy controls. JARID2 and ATXN1 levels were measured using four and three primer pairs targeting the transcripts, respectively (JARID2-1, -2, -3 and -4, and ATXN1-1, -2 and -3). Primer sequences are given in Additional file1: Table S1). JARID2 expression level was significantly reduced in the patients compared to the controls (p ≤ 0.01), while the ATXN1 expression level was not significantly altered (p ≤ 0.1). Ctrl, Control; Pt, Patient.

Mentions:
Expression of JARID2 and ATXN1 measured by RT-PCR was analyzed in the four patients that carried a deletion involving the gene(s) (Patients 1–4 and Patients 1–3 and 5, respectively) and in eight healthy controls, using RNA from leucocytes. The expression levels of JARID2 and ATXN1 were normalized to the levels of the three housekeeping genes, HPRT, PPIB and HMBS, which showed the most homogenous expression in the five patients among totally ten control genes analyzed. JARID2 expression was significantly reduced in our patients compared to controls (p ≤ 0.01) (Figure4A). ATXN1 expression in the patients was not significantly different from controls (p ≤ 0.1), but a trend towards reduced expression was observed (Patients 2 and 3 had a reduced expression level) (Figure4B).

Figure 4: Expression levels of JARID2 (A) and ATXN1 (B) in leucocytes from our four patients with deletion of one or both of these genes (Patients 1-4 and Patients 1-3 and 5, respectively), compared with eight healthy controls. JARID2 and ATXN1 levels were measured using four and three primer pairs targeting the transcripts, respectively (JARID2-1, -2, -3 and -4, and ATXN1-1, -2 and -3). Primer sequences are given in Additional file1: Table S1). JARID2 expression level was significantly reduced in the patients compared to the controls (p ≤ 0.01), while the ATXN1 expression level was not significantly altered (p ≤ 0.1). Ctrl, Control; Pt, Patient.

Mentions:
Expression of JARID2 and ATXN1 measured by RT-PCR was analyzed in the four patients that carried a deletion involving the gene(s) (Patients 1–4 and Patients 1–3 and 5, respectively) and in eight healthy controls, using RNA from leucocytes. The expression levels of JARID2 and ATXN1 were normalized to the levels of the three housekeeping genes, HPRT, PPIB and HMBS, which showed the most homogenous expression in the five patients among totally ten control genes analyzed. JARID2 expression was significantly reduced in our patients compared to controls (p ≤ 0.01) (Figure4A). ATXN1 expression in the patients was not significantly different from controls (p ≤ 0.1), but a trend towards reduced expression was observed (Patients 2 and 3 had a reduced expression level) (Figure4B).

Bottom Line:
The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients.Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Background: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes.

Methods and results: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.